Nerve growth factor (NGF) was first described by Levi-Montalcini (J. Exp Zool., 116:321-362 (1951)) as an activity secreted by a mouse sarcoma tumor implanted into a chick embryo. Both sensory ganglion and sympathetic ganglion neurons grew neurites into the sarcoma, which also supported the growth of peripheral neurons in culture. The factor, purified to homogeneity from mouse submandibular glands in 1956 by Levi-Montalcini and Cohen (Proc. Natl. Acad. Sci. USA, 42:571 (1956)) consists of a complex (referred to as 7S NGF, from its sedimentation coefficient) comprised of three different subunits. NGF's neurotrophic activity resides entirely within the .beta.-subunit (hereinafter referred to as NGF), a dimer consisting of two equivalent monomers of approximately 13,000 dalton molecular weight.
A role for NGF as a neurotrophic factor in the peripheral nervous system (PNS) was rapidly established through both in vitro and in vivo experiments (Levi-Montalcini and Angeletti, Physiol. Rev., 48:534-569 (1968); Johnson, et al., Science, 210:916-918 (1980)). These studies demonstrated that sympathetic neurons of the PNS have an absolute requirement for NGF for survival throughout life, while many sensory neurons require NGF during certain periods of development. As an extrapolation of these early findings, NGF and related neurotrophic factors have been shown recently to be useful in the treatment of sensory and autonomic neuropathies (Kaplan, et al., Science, 252:554-558 (1991)). More specifically, NGF prevents the development of small-fiber sensory neuropathies that result from the use of taxol, a chemotherapeutic agent (Apfel, et al., Ann. Neurol., 29:87-90 (1991)). NGF is also efficacious against the development of large-fiber sensory neuropathies resulting from the anticancer drug cisplatin, and in an animal model of diabetes-induced neuropathy (Apfel, et al., Ann. Neurol., 31:76-80 (1992)).
NGF is synthesized in the periphery by the non-neuronal target tissues innervated by the NGF-dependent neurons. Upon binding of NGF to its receptor, the NGF receptor complex is internalized by the neuron and retrogradely transported back to the neuron cell body. NGF's intracellular mechanism of action is not yet fully understood.
It was not until 1983 that NGF was detected in the central nervous system (CNS) (Ayer-LeLievre, et al., Medical Biology, 61:296-304 (1983)). This discovery was preceded by the demonstration that the cholinergic neurons of the basal forebrain are responsive to NGF (Schwab, et al., Brain Res., 168:473-483 (1979)). These neurons possess NGF receptors which are undistinguishable from the NGF receptors in the periphery. As in the PNS, NGF is synthesized by the target regions of the sensitive neurons, the hippocampus and the neocortex. NGF secreted by these target regions binds to its receptor(s) on NGF-dependent neurons, and is required for the development and survival of these neurons.
In animal models, lesions of the septo-hippocampal neuronal pathway, which connects the neurons of the basal forebrain to the hippocampus, results in the degeneration of the neurons in the medial septal nucleus, due to the lack of trophic support that is normally provided by hippocampal NGF. This neuronal degeneration can be prevented by administration of NGF into the cerebrospinal fluid (CSF) of the animals via a miniosmotic pump (Gage, et al., J. Comp. Neurol., 269:147-155 (1988); Hagg, et al., Exp. Neurol., 101:303-312 (1988); Kromer, et al., Science, 235:214-216 (1987)). NGF also enhances the ability of brain cholinergic neurons to survive a chemical insult. In animals with atrophied or lesioned basal forebrain cholinergic neurons, NGF has been shown to reverse the associated behavioral impairment (Fisher, et al., J. Neurosci., 11:1889-1906 (1991); Tuszynski, et al., Ann. Neurol., 30:625-636 (1991)).
Even though there is no direct evidence for a reduced level of NGF in neurodegenerative disorders such as Alzheimer's disease (AD), the sensitivity of brain cholinergic neurons to NGF treatment is specially interesting, since these neurons are consistently depleted in AD. In fact, recent clinical findings in humans support the interpretation that treatment with NGF is useful in the treatment of AD (Olson, et al., J. Neural. Transm., (P-D Sect) 4:79 (1992)).
NGF produces its effects by binding to receptors in the cytoplasmic membrane of NGF-sensitive neurons. Two types of NGF receptors have been identified to date. The low affinity NGF receptor (Johnson, et al., Cell, 47:545-554 (1986)), known as p75 because it has a molecular weight of about 75,000 dalton, binds NGF with an affinity (K.sub.D =10.sup.-9 M) several orders of magnitude lower than that associated with NGF receptors on neurons (K.sub.D =10.sup.-11 M). The p75 receptor is a single peptide chain of about 400 amino acid residues, with a single membrane-spanning domain separating the NFG-binding extracellular domain from a shorter cytoplasmic domain and with no obvious consensus sequence for any known signal transduction mechanism (Large, et al., Neuron, 2:1123-1124 (1989)).
More recently, a new NGF receptor (referred to as p140.sup.trkA or simply trkA or trk) has been identified and cloned (Kaplan, et al., Science, 252:554-558 (1991); Klein, et al., Cell, 65:189-197 (1991)). The trk receptor is also a single peptide chain, somewhat larger than p75 (about 790 amino acids) with a single membrane-spanning domain. The intracellular C terminus of trk contains a tyrosine kinase consensus sequence; binding of NGF to trk induces autophosphorylation of trk and stimulates tyrosine kinase activity intracellularly (Kaplan, et al., Science, 252:554-558 (1991)).
It appears that the actions of NGF on NGF-responsive cells are mediated by the trk receptor (Kaplan, et al., Science., 252:554-558 (1991); Barker, et al., Mol. Cell, Biochem., 110:1-15 (1992)). The role of the p75 receptor is less clear. It may be part of a multicomponent NGF receptor complex in some cell types, while perhaps being less critical in others (Bothwell, et al., Cell, 65:915-918 (1991); Meakin and Shooter, TINS, 15:323-331 (1992)). Of particular interest is a recent finding that glial cells, which express only p75 receptor and no trk, are capable of internalizing and degrading significant amounts of NGF, leading to the speculation that this is a regulatory mechanism of the amount of NGF available to neurons (Kahle and Hertel, J. Biol. Chem., 267:13917-13923 (1992)). This would imply that blocking access of NGF to the p75 receptor will increase the amount of NGF available to neurons.